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Aim Patients with heart failure with reduced ejection fraction and low systolic blood pressure (SBP) have high mortality, hospitalizations, and poorly tolerate evidence-based medical treatment. Omecamtiv mecarbil may be particularly helpful in such patients. This study examined its efficacy and tolerability in patients with SBP ≤100 mmHg enrolled in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC-HF). Methods and results The GALACTIC-HF enrolled patients with baseline SBP ≥85 mmHg with a primary outcome of time to cardiovascular death or first heart failure event. In this analysis, patients were divided according to their baseline SBP (≤100 vs. >100 mmHg). Among the 8232 analysed patients, 1473 (17.9%) had baseline SBP ≤100 mmHg and 6759 (82.1%) had SBP >100 mmHg. The primary outcome occurred in 715 (48.5%) and 2415 (35.7%) patients with SBP ≤100 and >100 mmHg, respectively. Patients with lower SBP were at higher risk of adverse outcomes. Omecamtiv mecarbil, compared with placebo, appeared to be more effective in reducing the primary composite endpoint in patients with SBP ≤100 mmHg [hazard ratio (HR), 0.81; 95% confidence interval (CI), 0.70–0.94] compared with those with SBP >100 mmHg (HR, 0.95; 95% CI, 0.88–1.03; P-value for interaction = 0.051). In both groups, omecamtiv mecarbil did not change SBP values over time and did not increase the risk of adverse events, when compared with placebo. Conclusion In GALACTIC-HF, risk reduction of heart failure outcomes with omecamtiv mecarbil compared with placebo was large and significant in patients with low SBP. Omecamtiv mecarbil did not affect SBP and was well tolerated independent of SBP values.

Aims Surveillance imaging is often used to detect remodelling, a change in cardiac geometry, and/or function; however, there are limited data in patients with chronic heart failure (HF). We sought to characterize cardiac remodelling in patients with chronic HF and evaluate its association with outcome. Methods and results A prospective cohort of patients at risk for HF or with chronic HF underwent cardiac magnetic resonance (CMR) at baseline and 1 year. Ventricular function, volumes, mass, left atrial volume, global longitudinal strain, and myocardial scar were measured. The primary outcome was a composite of death or cardiovascular hospitalization up to 5 years from the 1 year scan. Cox regression was used to identify 1 year CMR predictors of outcome after adjusting for baseline risk. A total of 262 patients (median age 68 years, 57% males) including 96 at risk for HF, 97 with HF and preserved ejection fraction, and 69 with HF and reduced ejection fraction were included. In the patients with HF, 55 events were identified during follow‐up. After adjustment for baseline clinical risk, Cox proportion hazard regressions only identified 1 year change in left ventricular (LV) mass index as a CMR predictor of outcome, adjusted hazard ratio 1.21 (1.02, 1.44) per 10% increase, P = 0.031. Cardiac remodelling defined as a 1 year change in LV mass index ≥15% was observed in 35% of patients with HF. Patients with adverse remodelling of LV mass index had more events on Kaplan–Meier analyses compared to those with no remodelling, log‐rank P = 0.004 for overall cohort, P = 0.035 for heart failure with preserved ejection fraction and P = 0.035 for heart failure and reduced ejection fraction. Conclusions Cardiac remodelling is common during serial CMR assessment of patients with chronic HF. Change in LV mass predicted long‐term outcomes whereas change in left ventricular ejection fraction did not.

Background: Angiotensin receptor neprilysin inhibitor (ARNi) therapy improves clinical outcomes in patients with heart failure and reduced left ventricular ejection fraction. However, ARNi therapy uptake remains modest, potentially in part due to perceived cost considerations of early transition from angiotensin converting enzyme inhibitor or angiotensin receptor blocker therapy. Methods: We constructed a decision-analytic Markov model to assess cost-effectiveness of 3 different ARNi initiation strategies according to timing of initiation: (1) de novo, or immediate initiation at baseline, (2) Early or after 3 months, or (3) Late, or after 9 months. Initiation strategies were compared with (4) current care, with utilization of ARNi derived from a large observational database. Total costs, quality-adjusted life-years (QALYs), and the incremental cost-effectiveness ratio (ICER) were estimated over a 5-year time horizon in the base case analysis. Results: Current care was associated with the lowest total cost (CAD$26,664) and accrued benefit (3.28 QALYs). The de novo strategy yielded an ICER of $34,727 per QALY gained, whereas Early and Late initiation strategies yielded a less favourable ICER per QALY gained of $35,871 and $40,234, respectively. The model was most sensitive to the cost of ARNi therapy. Conclusion: A strategy of de novo ARNi initiation is economically attractive and becomes less favourable as the delay of initiation increases. Our results suggest that ARNi therapy should be initiated as soon as possible for patients with heart failure and reduced left ventricular ejection fraction. Résumé: Contexte: Le traitement par un antagoniste des récepteurs de l’angiotensine/inhibiteur de la néprilysine (ARNI) améliore les résultats cliniques chez les patients présentant une insuffisance cardiaque et une fraction d’éjection ventriculaire gauche réduite. L’adoption d’un tel traitement demeure toutefois modeste, peut-être en partie à cause des perceptions quant au coût associé à la substitution précoce d’un inhibiteur de l’enzyme de conversion de l’angiotensine ou d’un antagoniste des récepteurs de l’angiotensine. Méthodologie: Nous avons mis au point un modèle de Markov appliqué à l’analyse décisionnelle afin d’évaluer le rapport coût-efficacité de trois stratégies d’instauration d’un traitement par un ARNI, selon le moment de la mise en route : 1) instauration de novo, c’est-à-dire instauration immédiate dès le départ; 2) instauration précoce (après trois mois); ou 3) instauration tardive (après neuf mois). Les stratégies d’instauration ont été comparées à 4) la norme de soins actuelle, l’utilisation des ARNI étant dérivée d’une importante base de données observationnelles. Dans l’analyse du scénario de référence, les coûts totaux, les années de vie pondérées par la qualité (QALY pour quality-adjusted life-years) et le rapport coût-efficacité différentiel (RCED) ont été estimés sur une période de cinq ans. Résultats: La norme de soins actuelle était associée au coût le plus faible (26 664 $CAD) et à un bienfait cumulé (3,28 QALY). La stratégie de novo a donné lieu à un RCED de 34 727 $ par QALY gagnée, tandis que les RCED des stratégies d’instauration précoce et tardive étaient moins favorables et s’établissaient respectivement à 35 871 $ et à 40 234 $. Le modèle s’est révélé plus sensible au coût du traitement par un ARNI. Conclusion: La mise en route d’un traitement par un ARNI de novo est attrayante sur le plan financier, et devient de moins en moins intéressante à mesure que le temps passe. Nos résultats indiquent qu’il faudrait instaurer le traitement par un ARNI le plus rapidement possible chez les patients présentant une insuffisance cardiaque et une fraction d’éjection ventriculaire gauche réduite.

Background: In the DAPA-HF trial (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure), dapagliflozin, added to guideline-recommended therapies, reduced the risk of mortality and heart failure (HF) hospitalization. We examined the frequency and significance of episodes of outpatient HF worsening, requiring the augmentation of oral therapy, and the effects of dapagliflozin on these additional events. Methods: Patients in New York Heart Association functional class II to IV, with a left ventricular ejection fraction ≤40% and elevation of NT-proBNP (N-terminal pro-B-type natriuretic peptide), were eligible. The primary outcome was the composite of an episode of worsening HF (HF hospitalization or an urgent HF visit requiring intravenous therapy) or cardiovascular death, whichever occurred first. An additional prespecified exploratory outcome was the primary outcome plus worsening HF symptoms/signs leading to the initiation of new, or the augmentation of existing, oral treatment. Results: Overall, 36% more patients experienced the expanded, in comparison with the primary, composite outcome. In the placebo group, 684 of 2371 (28.8%) patients and, in the dapagliflozin group, 527 of 2373 (22.2%) participants experienced the expanded outcome (hazard ratio, 0.73 [95% CI, 0.65–0.82]; P Conclusion: In DAPA-HF, outpatient episodes of HF worsening were common, were of prognostic importance, and were reduced by dapagliflozin. Registration: URL: https://www.clinicaltrials.gov ; Unique Identifier: NCT03036124.

Background Transthyretin amyloidosis cardiomyopathy (ATTR-CM) patients are often older and may be at risk for obstructive epicardial coronary artery disease (oeCAD). While ATTR-CM may cause small vessel coronary disease, the prevalence and clinical significance of oeCAD is not well described. Methods and results The prevalence and incidence of oeCAD and its association with all-cause mortality and hospitalization among 133 ATTR-CM patients with ≥ 1-year follow-up was evaluated. The mean age was 78 ± 9 years, 119 (89%) were male, 116 (87%) had wild-type and 17 (13%) had hereditary subtypes. Seventy-two (54%) patients underwent oeCAD investigations, with 30 (42%) receiving a positive diagnosis. Among patients with a positive oeCAD diagnosis, 23 (77%) were diagnosed prior to ATTR-CM diagnosis, 6 (20%) at the time of ATTR-CM diagnosis, and 1 (3%) after ATTR-CM diagnosis. Baseline characteristics between patients with and without oeCAD were similar. Among patients with oeCAD, only 2 (7%) required additional investigations, intervention or hospitalization after ATTR-CM diagnosis. After a median follow-up of 27 months there were 37 (28%) deaths in the study population, including 5 patients with oeCAD (17%). Fifty-six (42%) patients in the study population required hospitalization, including 10 patients with oeCAD (33%). There was no significant difference in the rates of death or hospitalization among ATTR-CM patients with and without oeCAD, and oeCAD was not significantly associated with either outcome by univariable regression analysis. Conclusions While oeCAD is prevalent in ATTR-CM patients, this diagnosis is frequently known at time of ATTR-CM diagnosis and characteristics are similar to patients without oeCAD.

Hypertension Canada's 2020 guidelines for the prevention, diagnosis, risk assessment, and treatment of hypertension in adults and children provide comprehensive, evidence-based guidance for health care professionals and patients. Hypertension Canada develops the guidelines using rigourous methodology, carefully mitigating the risk of bias in our process. All draft recommendations undergo critical review by expert methodologists without conflict to ensure quality. Our guideline panel is diverse, including multiple health professional groups (nurses, pharmacy, academics, and physicians), and worked in concert with experts in primary care and implementation to ensure optimal usability. The 2020 guidelines include new guidance on the management of resistant hypertension and the management of hypertension in women planning pregnancy.

International audience; In this update, we focus on selected topics of high clinical relevance for health care providers who treat patients with heart failure (HF), on the basis of clinical trials published after 2017. Our objective was to review the evidence, and provide recommendations and practical tips regarding the management of candidates for the following HF therapies: (1) transcatheter mitral valve repair in HF with reduced ejection fraction; (2) a novel treatment for transthyretin amyloidosis or transthyretin cardiac amyloidosis; (3) angiotensin receptor-neprilysin inhibition in patients with HF and preserved ejection fraction (HFpEF); and (4) sodium glucose cotransport inhibitors for the prevention and treatment of HF in patients with and without type 2 diabetes. We emphasize the roles of optimal guideline-directed medical therapy and of multidisciplinary teams when considering transcatheter mitral valve repair, to ensure excellent evaluation and care of those patients. In the presence of suggestive clinical indices, health care providers should consider the possibility of cardiac amyloidosis and proceed with proper investigation. Tafamidis is the first agent shown in a prospective study to alter outcomes in patients with transthyretin cardiac amyloidosis. Patient subgroups with HFpEF might benefit from use of sacubitril/valsartan, however, further data are needed to clarify the effect of this therapy in patients with HFpEF. Sodium glucose cotransport inhibitors reduce the risk of incident HF, HF-related hospitalizations, and cardiovascular death in patients with type 2 diabetes and cardiovascular disease. A large clinical trial recently showed that dapagliflozin provides significant outcome benefits in well treated patients with HF with reduced ejection fraction (left ventricular ejection fraction ≤ 40%), with or without type 2 diabetes.

BACKGROUND Cardiac retransplantation accounts for approximately 3% of cardiac transplantation and is considered a risk factor for increased mortality. However, factors inherent to retransplantation including previous sternotomy, sensitization, and renal dysfunction may account for the increased mortality. We assessed whether retransplantation was associated with all-cause mortality after adjusting for such patient risk factors. METHODS We conducted a retrospective cohort study of adult and pediatric patients enrolled in the United Network for Organ Sharing database. We identified patients undergoing cardiac retransplantation based on transplant listing diagnosis and history of previous transplant. We used propensity-score matching to identify a matched cohort undergoing initial heart transplantation. RESULTS In total, 62,112 heart transplant recipients were identified, with a mean age 46.6 ± 19.1 years. Of these, 2,202 (3.4%) underwent late cardiac retransplantation (>1 year after initial transplant and not for acute rejection). Compared with a matched group of patients undergoing initial heart transplantation, patients undergoing late retransplantation had comparable rates of all-cause mortality at 1 year (13.6% vs 13.8%, p = 0.733). In addition, overall mortality was not significantly different after matching (unadjusted hazard ratio [HR] 1.08, p = 0.084). In contrast, patients undergoing retransplantation within 1 year of initial transplant or for acute rejection remained at increased risk of mortality post-transplant after similar matching (unadjusted HR 1.79, p CONCLUSIONS After matching for comorbidities, late retransplantation in the adult population was not associated with an increase in all-cause mortality. Our findings highlight the importance of assessing indication acuity and comorbid conditions when considering retransplant candidacy.

Objectives The authors investigated the impact of coronary artery bypass grafting (CABG) on first and recurrent hospitalization in this population. Background In the STICH (Surgical Treatment for Ischemic Heart Failure) trial, CABG reduced all-cause death and hospitalization in patients with and ischemic cardiomyopathy and left ventricular ejection fraction Methods A total of 1,212 patients were randomized (610 to CABG + optimal medical therapy [CABG] and 602 to optimal medical therapy alone [MED] alone) and followed for a median of 9.8 years. All-cause and cause-specific hospitalizations were analyzed as time-to-first-event and as recurrent event analysis. Results Of the 1,212 patients, 757 died (62.4%) and 732 (60.4%) were hospitalized at least once, for a total of 2,549 total all-cause hospitalizations. Most hospitalizations (66.2%) were for cardiovascular causes, of which approximately one-half (907 or 52.9%) were for heart failure. More than 70% of all hospitalizations (1,817 or 71.3%) were recurrent events. The CABG group experienced fewer all-cause hospitalizations in the time-to-first-event (349 CABG vs. 383 MED, adjusted hazard ratio [HR]: 0.85; 95% confidence interval [CI]: 0.74 to 0.98; p = 0.03) and in recurrent event analyses (1,199 CABG vs. 1,350 MED, HR: 0.78, 95% CI: 0.65 to 0.94; p Conclusions CABG reduces all-cause, CV, and HF hospitalizations in time-to-first-event and recurrent event analyses. (Comparison of Surgical and Medical Treatment for Congestive Heart Failure and Coronary Artery Disease [STICH]; NCT00023595)

Introduction: Heart failure and mildly reduced ejection fraction (HFmrEF) is associated with a favourable prognosis compared heart failure with reduced EF. However, HFmrEF may be a transitory state and serial imaging might clarify if these patients demonstrate an increasing, decreasing or stable EF. Hypothesis: LVEF trajectory can identify sub-groups of patients with HFmrEF with different prognosis. Materials and Methods: Patients with a diagnosis of HF and at least two echocardiograms performed ≥6 months apart were included if the LVEF measured 40-49% on the second study. They were classified based on change from their first echocardiogram as: a) HFmrEF-Incr if LVEF had increased ≥ 10% (n=450), b) HFmrEF-Dec if LVEF had decreased ≥10% (n=512), or c) HFmrEF-stable if they did not meet the other criteria (n=389). The primary outcome was a composite of all-cause mortality or cardiovascular hospitalization (ACM/CVH). Associations with time to first event were assessed with multivariable Cox analyses adjusted for age, medical history, and medications. Results: In total, 1351 patients with HFmrEF were included (median age 74, 35.8% women). During a median follow-up of 15.3 months, ACM/CVH occurred in 811 patients (324 ACM, 487 CVH). HFmrEF-Incr was associated with a lower incidence of ACM/CVH compared to patients with HFmrEF-Stable (adjusted HR 0.72, 95% CI 0.59 - 0.87, p Conclusions: Patients with HFmrEF and positive trajectory of LVEF were less likely to experience adverse outcomes, while those with a negative LVEF trajectory demonstrated a trend to higher risk. Categories based on LVEF trajectory provide clinically meaningful information and may help physicians make decisions regarding the need to pursue more aggressive medical therapy and surveillance.

Heart failure (HF), and especially HF with preserved ejection fraction (HFpEF), remains a challenging condition to define. The heterogenous nature of this population may be related to a variety of underlying etiologies interacting myocardial dysfunction.Alberta HEART study was a prospective, observational cohort that enrolled participants along the spectrum of heart failure including: healthy controls, people at risk of HF, and patients with HF and preserved (HFpEF) or reduced ejection fraction (HFrEF). We aimed to explore phenotypes of patients with HF and at-risk of developing HF. Utilising 27 detailed clinical, echocardiographic and biomarker variables, latent class analysis with and without multiple imputation was undertaken to identify distinct clinical phenotypes.Of 621 participants, 191 (30.8%) and 169 (27.2%) were adjudicated by cardiologists to have HFpEF and HFrEF respectively. In the overall cohort, latent class analysis identified four distinct phenotypes. Phenotype A (n=152, 24.5%) was a healthy and low risk group. Phenotype B (n=129, 20.8%) demonstrated increased left ventricular mass and end-diastolic volumes, with elevated natriuretic peptides and clinical features of congestion. Phenotype C (n=128, 20.6%) was primarily characterised by obesity (80%) and normal indexed cardiac chamber sizes, low natriuretic peptide levels and minimal features of congestion. Phenotype D (n=212, 34.1%) consisted of elderly patients with clinical features of congestions. Phenotypes B and D demonstrated the highest risk of mortality and hospitalization over a median follow-up of 3.7 years.Phenotypes with congestive features demonstrated increased risk profiles. Heart failure is a heterogenous classification which requires further work to appropriately categorise patients based on the underlying etiology or mechanism of impairment.

Importance: Sodium glucose cotransporter 2 inhibitors reduce morbidity and mortality in patients with heart failure and reduced ejection fraction (HFrEF). Clinicians may find estimates of the projected long-term benefits of sodium glucose cotransporter 2 inhibitors a helpful addition to clinical trial results when communicating the benefits of this class of drug to patients. Objective: To estimate the projected long-term treatment effects of dapagliflozin in patients with HFrEF over the duration of a patient’s lifetime. Design, Setting, and Participants: Exploratory analysis was performed of Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF), a phase 3 randomized, placebo-controlled clinical trial conducted at 410 sites in 20 countries. Patients with an ejection fraction less than or equal to 40% in New York Heart Association functional classification II to IV and elevated plasma levels of N-terminal pro B-type natriuretic peptide were enrolled between February 15, 2017, and August 17, 2018, with final follow-up on June 6, 2019. Mean (SD) duration of follow-up was 17.6 (5.2) months. Interventions: Dapagliflozin, 10 mg, once daily vs placebo in addition to standard therapy. Main Outcomes and Measures: The primary composite outcome was time to first hospitalization for heart failure, urgent heart failure visit requiring intravenous therapy, or cardiovascular death. The trial results were extrapolated to estimate the projected long-term treatment effects of dapagliflozin over the duration of a patient’s lifetime for the primary outcome and the secondary outcome of death from any cause. Results: A total of 4744 patients (1109 women [23.4%]; 3635 men [76.6%]) were randomized in DAPA-HF, with a mean (SD) age of 66.3 (10.9) years. The extrapolated mean event-free survival for an individual aged 65 years from a primary composite end point event was 6.2 years for placebo and 8.3 years for dapagliflozin, representing an event-free survival time gain of 2.1 years (95% CI, 0.8-3.3 years; P = .002). When considering death from any cause, mean extrapolated life expectancy for an individual aged 65 years was 9.1 years for placebo and 10.8 years for dapagliflozin, with a gain in survival of 1.7 years (95% CI, 0.1-3.3; P = .03) with dapagliflozin. Similar results were seen when extrapolated across the age range studied. In analyses of subgroups of patients in DAPA-HF, consistent benefits were seen with dapagliflozin on both event-free and overall survival. Conclusions and Relevance: These findings indicate that dapagliflozin provides clinically meaningful gains in extrapolated event-free and overall survival. These findings may be helpful in communicating the benefits of this treatment to patients with HFrEF. Trial registration: ClinicalTrials.gov Identifier: NCT03036124.

Objectives: This study sought to investigate the efficacy and safety of dapagliflozin in Black and White patients with heart failure (HF) with reduced ejection fraction (HFrEF) enrolled in DAPA-HF (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure). Background: Black patients may respond differently to certain treatments for HFrEF than White patients. Methods: Patients with New York Heart Association functional class II to IV with an ejection fraction of ≤40% and elevated N-terminal pro–B-type natriuretic peptide were eligible for DAPA-HF. Because >99% of Black patients were randomized in the Americas, this post hoc analysis considered Black and White patients enrolled only in North and South America. The primary outcome was the composite of a worsening HF event (HF hospitalization or urgent HF visit requiring intravenous therapy) or cardiovascular death. Results: Of the 4,744 patients randomized in DAPA-HF, 1,494 (31.5%) were enrolled in the Americas. Of these, 1,181 (79.0%) were White, and 225 (15.1%) were Black. Black patients had a higher rate of worsening HF events, but not mortality, compared with White patients. Compared with placebo, dapagliflozin reduced the risk of the primary endpoint similarly in Black patients (HR: 0.62; 95% CI: 0.37-1.03) and White patients (HR: 0.68; 95% CI: 0.52-0.90; P-interaction = 0.70). Consistent benefits were observed for other prespecified outcomes, including the composite of total (first and repeat) HF hospitalizations and cardiovascular death (P-interaction = 0.43) and Kansas City Cardiomyopathy Questionnaire total symptom score. Study drug discontinuation and serious adverse events were not more frequent in the dapagliflozin group than in the placebo group in either Black or White patients. Conclusions: Dapagliflozin reduced the risk of worsening HF and cardiovascular death, and it improved symptoms, similarly in Black and White patients without an increase in adverse events. (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure [DAPA-HF]; NCT03036124)

Aims To identify variables predicting ejection fraction (EF) recovery and characterize prognosis of heart failure (HF) patients with EF recovery (HFrecEF). Methods and results Retrospective study of adults referred for ≥2 echocardiograms separated by ≥6 months between 2008 and 2016 at the two largest echocardiography centres in Alberta who also had physician-assigned diagnosis of HF. Of 10 641 patients, 3124 had heart failure reduced ejection fraction (HFrEF) (EF ≤ 40%) at baseline: while mean EF declined from 30.2% on initial echocardiogram to 28.6% on the second echocardiogram in those patients with persistent HFrEF (defined by Conclusion HFrecEF patients tended to be younger, female, and were more likely to have hypertension, atrial fibrillation, or cancer. HFrecEF patients have a substantially better prognosis compared to those with persistent HFrEF, even after multivariable adjustment, and female patients exhibit lower mortality risk than men within each subgroup (HFrecEF and persistent HFrEF) even after multivariable adjustment.

The tolerability and utility of combination doxycycline and ursodeoxycholic acid (ursodiol) amyloid fibril disruption therapy for transthyretin cardiac amyloidosis (ATTR CA) in clinical practice is poorly described.We report the clinical experience of 53 ATTR CA patients treated with doxycycline and ursodiol. Six patients (11%) did not tolerate the therapy owing to dermatologic and gastrointestinal effects. Of those remaining, the median follow-up was 22 months (range 8-30), mean age was 71 ± 11years, 41 (87%) were male, and 42 (89%) had wild-type and 5 (11%) mutant ATTR. Five patients (11%) died during follow-up. There was no significant change in New York Heart Association (NYHA) functional class, cardiac biomarkers, or echocardiographic parameters during follow-up. Left ventricular (LV) global longitudinal systolic strain (GLS) improved in 16 patients (38%) (-12 ± 4% to -17 ± 4%; P.01). Patients whose LV GLS improved were significantly younger and had lower NYHA functional class, troponin-T, N-terminal pro-B-type natriuretic peptide (BNP), and baseline LV GLS levels compared with those whose LV GLS did not improve. Troponin-T improved in follow-up for patients whose LV GLS improved (35 ± 21 to 20 ± 14 ng/L; P = .06).Doxycycline and ursodiol therapy for treatment of ATTR CA was tolerable and was associated with stabilized markers of disease progression. LV GLS improved in patients with less advanced disease.

International audience; In this update of the Canadian Cardiovascular Society heart failure (HF) guidelines, we provide comprehensive recommendations and practical tips for the pharmacologic management of patients with HF with reduced ejection fraction (HFrEF). Since the 2017 comprehensive update of the Canadian Cardiovascular Society guidelines for the management of HF, substantial new evidence has emerged that has informed the care of these patients. In particular, we focus on the role of novel pharmacologic therapies for HFrEF including angiotensin receptor-neprilysin inhibitors, sinus node inhibitors, sodium glucose transport 2 inhibitors, and soluble guanylate cyclase stimulators in conjunction with other long established HFrEF therapies. Updated recommendations are also provided in the context of the clinical setting for which each of these agents might be prescribed; the potential value of each therapy is reviewed, where relevant, for chronic HF, new onset HF, and for HF hospitalization. We define a new standard of pharmacologic care for HFrEF that incorporates 4 key therapeutic drug classes as standard therapy for most patients: an angiotensin receptor-neprilysin inhibitor (as first-line therapy or after angiotensin converting enzyme inhibitor/angiotensin receptor blocker titration); a β-blocker; a mineralocorticoid receptor antagonist; and a sodium glucose transport 2 inhibitor. Additionally, many patients with HFrEF will have clinical characteristics for which we recommended other key therapies to improve HF outcomes, including sinus node inhibitors, soluble guanylate cyclase stimulators, hydralazine/nitrates in combination, and/or digoxin. Finally, an approach to management that integrates prioritized pharmacologic with nonpharmacologic and invasive therapies after a diagnosis of HFrEF is highlighted.

Aims: In heart failure with reduced ejection fraction (HFrEF), there is an ‘obesity paradox’, where survival is better in patients with a higher body mass index (BMI) and weight loss is associated with worse outcomes. We examined the effect of a sodium–glucose co-transporter 2 inhibitor according to baseline BMI in the Dapagliflozin And Prevention of Adverse-outcomes in Heart Failure trial (DAPA-HF). Methods and results: Body mass index was examined using standard categories, i.e. underweight (2); normal weight (18.5–24.9 kg/m2); overweight (25.0–29.9 kg/m2); obesity class I (30.0–34.9 kg/m2); obesity class II (35.0–39.9 kg/m2); and obesity class III (≥40 kg/m2). The primary outcome in DAPA-HF was the composite of worsening heart failure or cardiovascular death. Overall, 1348 patients (28.4%) were under/normal-weight, 1722 (36.3%) overweight, 1013 (21.4%) obesity class I and 659 (13.9%) obesity class II/III. The unadjusted hazard ratio (95% confidence interval) for the primary outcome with obesity class 1, the lowest risk group, as reference was: under/normal-weight 1.41 (1.16–1.71), overweight 1.18 (0.97–1.42), obesity class II/III 1.37 (1.10–1.72). Patients with class I obesity were also at lowest risk of death. The effect of dapagliflozin on the primary outcome and other outcomes did not vary by baseline BMI, e.g. hazard ratio for primary outcome: under/normal-weight 0.74 (0.58–0.94), overweight 0.81 (0.65–1.02), obesity class I 0.68 (0.50–0.92), obesity class II/III 0.71 (0.51–1.00) (P-value for interaction = 0.79). The mean decrease in weight at 8 months with dapagliflozin was 0.9 (0.7–1.1) kg (P < 0.001). Conclusion: We confirmed an ‘obesity survival paradox’ in HFrEF. We showed that dapagliflozin was beneficial across the wide range of BMI studied. Clinical Trial Registration: ClinicalTrials.gov NCT03036124.

The advent of newly available medical therapies for heart failure with reduced ejection fraction (HFrEF) has resulted in many potential therapeutic combinations, increasing treatment complexity. Publication of expert consensus guidelines and initiatives aimed to improve implementation of treatment has emphasized sequential stepwise initiation and titration of medical therapy, which is labour intensive. Data taken from heart failure registries show suboptimal use of medications, prolonged titration times, and consequently little change in dose intensity, all of which indicate therapeutic inertia. Recently published evidence indicates that 4 medication classes-renin-angiotensin-neprilysin inhibitors, β-blockers, mineralocorticoid antagonists, and sodium-glucose cotransporter inhibitors-which we refer to as Foundational Therapy, confer rapid and robust reduction in both morbidity and mortality in most patients with HFrEF and that they work in additive fashion. Additional morbidity and mortality may be observed following addition of several personalized therapies in specific subgroups of patients. In this review, we discuss mechanisms of action of these therapies and propose a framework for their implementation, based on several principles. These include the critical importance of rapid initiation of all 4 Foundational Therapies followed by their titration to target doses, emphasis on multiple simultaneous drug changes with each patient encounter, attention to patient-specific factors in choice of medication class, leveraging inpatient care, use of the entire health care team, and alternative (ie, virtual visits) modes of care. We have incorporated these principles into a Cluster Scheme designed to facilitate timely and optimal medical treatment for patients with HFrEF.

Aims The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is being tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC‐HF) trial. Here we describe the baseline characteristics of participants in GALACTIC‐HF and how these compare with other contemporary trials. Methods and results Adults with established HFrEF, New York Heart Association (NYHA) functional class ≥II, ejection fraction ≤35%, elevated natriuretic peptides and either current hospitalization for heart failure or history of hospitalization/emergency department visit for heart failure within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic‐guided dosing: 25, 37.5, or 50 mg bid). A total of 8256 patients [male (79%), non‐white (22%), mean age 65 years] were enrolled with a mean ejection fraction 27%, ischaemic aetiology in 54%, NYHA class II 53% and III/IV 47%, and median N‐terminal pro‐B‐type natriuretic peptide 1971 pg/mL. Heart failure therapies at baseline were among the most effectively employed in contemporary heart failure trials. GALACTIC‐HF randomized patients representative of recent heart failure registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure, Graphical representation of the GALACTIC‐HF trial design, enrolment and baseline characteristics. ACEi, angiotensin‐converting enzyme inhibitor; ARB, angiotensin receptor blocker; ARNi, angiotensin receptor–neprilysin inhibitor; CRT, cardiac resynchronization therapy (biventricular pacemaker); CV, cardiovascular; EF, ejection fraction; HFrEF, heart failure with reduced ejection fraction; ICD, implantable cardioverter defibrillator; NT‐proBNP, N‐terminal pro‐B‐type natriuretic peptide; NYHA, Hew York Heart Association; SBP, systolic blood pressure.

Importance Heart failure with reduced ejection fraction is a progressive clinical syndrome, and many patients’ condition worsen over time despite treatment. Patients with more severe disease are often intolerant of available medical therapies. Objective To evaluate the efficacy and safety of omecamtiv mecarbil for the treatment of patients with severe heart failure (HF) enrolled in the Global Approach to Lowering Adverse Cardiac Outcomes Through Improving Contractility in Heart Failure (GALACTIC-HF) randomized clinical trial. Design, Setting, and Participants The GALACTIC-HF study was a global double-blind, placebo-controlled phase 3 randomized clinical trial that was conducted at multiple centers between January 2017 and August 2020. A total of 8232 patients with symptomatic HF (defined as New York Heart Association symptom class II-IV) and left ventricular ejection fraction of 35% or less were randomized to receive omecamtiv mecarbil or placebo and followed up for a median of 21.8 months (range, 15.4-28.6 months). The current post hoc analysis evaluated the efficacy and safety of omecamtiv mecarbil therapy among patients classified as having severe HF compared with patients without severe HF. Severe HF was defined as the presence of all of the following criteria: New York Heart Association symptom class III to IV, left ventricular ejection fraction of 30% or less, and hospitalization for HF within the previous 6 months. Interventions Participants were randomized at a 1:1 ratio to receive either omecamtiv mecarbil or placebo. Main Outcomes and Measures The primary end point was time to first HF event or cardiovascular (CV) death. Secondary end points included time to CV death and safety and tolerability. Results Among 8232 patients enrolled in the GALACTIC-HF clinical trial, 2258 patients (27.4%; mean [SD] age, 64.5 [11.6] years; 1781 men [78.9%]) met the specified criteria for severe HF. Of those, 1106 patients were randomized to the omecamtiv mecarbil group and 1152 to the placebo group. Patients with severe HF who received omecamtiv mecarbil experienced a significant treatment benefit for the primary end point (hazard ratio [HR], 0.80; 95% CI, 0.71-0.90), whereas patients without severe HF had no significant treatment benefit (HR, 0.99; 95% CI, 0.91-1.08;P = .005 for interaction). For CV death, the results were similar (HR for patients with vs without severe HF: 0.88 [95% CI, 0.75-1.03] vs 1.10 [95% CI, 0.97-1.25];P = .03 for interaction). Omecamtiv mecarbil therapy was well tolerated in patients with severe HF, with no significant changes in blood pressure, kidney function, or potassium level compared with placebo. Conclusions and Relevance In this post hoc analysis of data from the GALACTIC-HF clinical trial, omecamtiv mecarbil therapy may have provided a clinically meaningful reduction in the composite end point of time to first HF event or CV death among patients with severe HF. These data support a potential role of omecamtiv mecarbil therapy among patients for whom current treatment options are limited. Trial Registration ClinicalTrials.gov Identifier:NCT02929329

Aims Concern about hypotension often leads to withholding of beneficial therapy in patients with heart failure and reduced ejection fraction (HFrEF). We evaluated the efficacy and safety of dapagliflozin, which lowers systolic blood pressure (SBP),according to baseline SBP in Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure trial (DAPA-HF). Methods and results Key inclusion criteria were: New York Heart Association Class II−IV, left ventricular ejection fraction ≤ 40%, elevated N-terminal pro-B-type natriuretic peptide level, and SBP ≥95 mmHg. The primary outcome was a composite of worsening heart failure or cardiovascular death. The efficacy and safety of dapagliflozin were examined using SBP as both a categorical and continuous variable. A total of 1205 patients had a baseline SBP, Graphical Abstract

Background Improving health‐related quality of life is an important goal in the management of patients with heart failure (HF). Defining health‐related quality of life changes over time in patients with HF with preserved (HFpEF) or reduced ejection fraction and showing their association with other important clinical events could support the use of health‐related quality of life as a measure of quantifying HF care. Methods and Results In the Alberta HEART (Heart Failure Aetiology and Analysis Team) cohort (n=621), patients were categorized into 4 subgroups: healthy controls (n=98), at risk (n=163), HFpEF (n=191), and HF with reduced ejection fraction (n=169). The change of the Kansas City Cardiomyopathy Questionnaire (KCCQ), EuroQOL 5 dimensions, and Functional Assessment of Cancer Therapy—Anemia over 12 months, and its association with a composite of death or rehospitalization within 3 years were assessed. At baseline, the KCCQ overall summary score was 73 (interquartile range, 53–86) in HFpEF and 78 (interquartile range, 56–90) in HF with reduced ejection fraction ( P =0.22). Overall, 30.5% of patients with HF experienced ≥5‐point improvements and 32.4% had ≥5‐point worsening in KCCQ overall summary score at 12 months, which did not differ between HFpEF and HF with reduced ejection fraction ( P =0.23). Clinical events were higher in patients with HF who had a decline in KCCQ over 12 months as compared with those with stable KCCQ scores (70.2% versus 52.0%, P =0.012). The results were similar for the Functional Assessment of Cancer Therapy—Anemia and EuroQOL 5 dimensions. Conclusions In patients with HF, the KCCQ quantified clinically meaningful changes over time, which were associated with important clinical outcomes in patients with HFpEF. Given the observed variability and prognostication in different patient trajectories, health‐related quality of life measures could be valuable for quantifying the quality of care in healthcare systems.

Aims The EMPERIAL (Effect of EMPagliflozin on ExeRcise ability and HF symptoms In patients with chronic heArt faiLure) trials evaluated the effects of empagliflozin on exercise ability and patient-reported outcomes in heart failure (HF) with reduced and preserved ejection fraction (EF), with and without type 2 diabetes (T2D), reporting, for the first time, the effects of sodium-glucose co-transporter-2 inhibition in HF with preserved EF (HFpEF). Methods and results HF patients with reduced EF (HFrEF) (≤40%, N = 312, EMPERIAL-Reduced) or preserved EF (>40%, N = 315, EMPERIAL-Preserved), with and without T2D, were randomized to empagliflozin 10 mg or placebo for 12 weeks. The primary endpoint was 6-minute walk test distance (6MWTD) change to Week 12. Key secondary endpoints included Kansas City Cardiomyopathy Questionnaire Total Symptom Score (KCCQ-TSS) and Chronic Heart Failure Questionnaire Self-Administered Standardized format (CHQ-SAS) dyspnoea score. 6MWTD median (95% confidence interval) differences, empagliflozin vs. placebo, at Week 12 were −4.0 m (−16.0, 6.0; P = 0.42) and 4.0 m (−5.0, 13.0; P = 0.37) in EMPERIAL-Reduced and EMPERIAL-Preserved, respectively. As the primary endpoint was non-significant, all secondary endpoints were considered exploratory. Changes in KCCQ-TSS and CHQ-SAS dyspnoea score were non-significant. Improvements with empagliflozin in exploratory pre-specified analyses of KCCQ-TSS responder rates, congestion score, and diuretic use in EMPERIAL-Reduced are hypothesis generating. Empagliflozin adverse events were consistent with those previously reported. Conclusion The primary outcome for both trials was neutral. Empagliflozin was well tolerated in HF patients, with and without T2D, with a safety profile consistent with that previously reported in T2D. Hypothesis-generating improvements in exploratory analyses of secondary endpoints with empagliflozin in HFrEF were observed.

Aims The aim of this study is to determine factors associated with long‐term recovery of left ventricular ejection fraction (LVEF) in patients with heart failure with reduced EF (HFrEF) and if further recovery also occurs in this group. Methods and results Among 621 participants enrolled in the Alberta Heart Failure Etiology and Analysis Team (HEART) Study, 316 with Stage C HF underwent comprehensive imaging and biomarker testing at enrolment and at 1‐year follow up. Using pre‐enrolment data, HF with recovered EF (HFrecEF) was defined as an absolute improvement ≥5% in LVEF from the prior lowest LVEF value, with a final LVEF value > 35% at or prior to study baseline. Participants with all LVEF > 40% were included for comparison. Hospitalization‐free survival to 5 years was performed. The median cohort age was 66 years, and time from diagnosis was 4 years; 82% were male patients. Of the 316 patients, 95 (30%) patients had HFrecEF and 56 (18%) patients pHFrEF. On multivariate analysis, only shorter duration of HF was predictive of HFrecEF status. Over 1 year, LVEF increased in the HFrecEF group 4.0% (0.15–7.90, P = 0.042) as compared with persistent HFrEF, who in turn demonstrated higher baseline serum high sensitivity Troponin‐T with further increase at follow up 0.55(0.33–0.86, P = 0.011). No change in any parameter in the HFpEF/HFmrEF group at follow up was observed. Conclusions Patients with HFrecEF demonstrate evidence of additional late improvement in LVEF and unchanged troponin levels, in contrast to those with persistent HFrEF, where LVEF does not improve and serum troponin rises over time. These data help to inform mechanisms relating to late LV remodelling.

This joint Canadian Heart Failure Society and the CCS Heart Failure guidelines report has been developed to provide a pan-Canadian snapshot of the current state of clinic-based ambulatory heart failure (HF) care in Canada with specific reference to elements and processes of care associated with quality and high performing health systems. It includes the viewpoints of persons with lived experience, patient care providers, and administrators. It is imperative to build on the themes identified in this survey, through engaging all health care professionals, to develop integrated and shared care models that will allow better patient outcomes. Several patient and organizational barriers to care were identified in this survey, which must inform the development of regional care models and pragmatic solutions to improve transitions for this patient population. Unfortunately, we were unsuccessful in incorporating the perspectives of primary care providers and internal medicine specialists who provide the majority of HF care in Canada, which in turn limits our ability to comment on strategies for capacity building outside the HF clinic setting. These considerations must be taken into account when interpreting our findings. Engaging all HF care providers, to build on the themes identified in this survey, will be an important next step in developing integrated and shared care models known to improve patient outcomes. Résumé: Ce rapport conjoint des lignes directrices de la Société canadienne d'insuffisance cardiaque et de la Société canadienne de cardiologie (SCC) sur l'insuffisance cardiaque a été élaboré pour fournir un aperçu pancanadien de l'état actuel des soins ambulatoires de l'insuffisance cardiaque (IC) en clinique au Canada, en se référant spécifiquement aux éléments et aux processus de soins associés à des systèmes de santé très performants et de qualité. Il comprend les points de vue de personnes ayant une expérience vécue de l'IC, de prestataires de soins aux patients et d'administrateurs. Il est impératif de s'appuyer sur les thématiques identifiées dans cette enquête, en y engageant tous les professionnels de la santé, pour développer des modèles de soins intégrés et partagés qui permettront de meilleurs pronostics pour les patients. Plusieurs obstacles relatifs aux patients et organisationnels dont il faudra se soucier ont été identifiés dans cette enquête, qui doit servir de base à l'élaboration de modèles de soins régionaux et de solutions pragmatiques pour améliorer les transitions pour cette population de patients. Malheureusement, nous n'avons pas réussi à intégrer les points de vue des prestataires de soins primaires et des spécialistes en médecine interne qui fournissent la majorité des soins en IC au Canada, ce qui limite notre capacité à commenter les stratégies de renforcement des capacités en dehors du cadre des cliniques d’IC. Ces considérations doivent être prises en compte lors de l'interprétation de nos conclusions. L'engagement de tous les prestataires de soins de santé en IC à s'appuyer sur les thématiques identifiées dans cette enquête constituera une prochaine étape importante dans le développement de modèles de soins intégrés et partagés connus pour améliorer le pronostic des patients.

Aims In the DAPA-HF trial, the SGLT2 inhibitor dapagliflozin reduced the risk of worsening heart failure (HF) and death in patients with HF and reduced ejection fraction. We examined whether this benefit was consistent in relation to background HF therapy. Methods and results In this post hoc analysis, we examined the effect of study treatment in the following yes/no subgroups: diuretic, digoxin, mineralocorticoid receptor antagonist (MRA), sacubitril/valsartan, ivabradine, implanted cardioverter-defibrillating (ICD) device, and cardiac resynchronization therapy. We also examined the effect of study drug according to angiotensin-converting enzyme inhibitor/angiotensin receptor blocker dose, beta-blocker (BB) dose, and MRA (≥50% and Conclusion The benefit of dapagliflozin was consistent regardless of background therapy for HF.

Background Right ventricular (RV) strain imaging using speckle-tracking echocardiography (STE) is a quantitative method of assessing RV systolic function that has demonstrated prognostic utility in patients with pulmonary hypertension (PH). However, its prognostic value for a large and mixed PH population remains poorly defined. Methods A systematic review and meta-analysis was performed using the MEDLINE, Embase and Cochrane Library databases for publications reporting the prognostic value of RV strain calculated using 2-dimensional STE in PH patients for the clinical endpoint of all-cause mortality. Results Screening of 687 publications yielded 10 that were included in the meta-analysis, representing data for 1,001 PH patients, among which 76% had pulmonary arterial hypertension with the remainder having a range of PH etiologies. The pooled free wall RV strain was -16.2% (95% CI -14.3--18.1, I 2 =94.1%, Q=102.8, p 2 =84.9%, Q=20, p 2 =0, Q=1.8, p=0.87, while the pooled unadjusted hazard ratio of RV strain as a continuous variable (per 1% change) was 1.14 (95% CI 1.11-1.8, p 2 =0, Q=2.0, p=0.85, and were superior to corresponding values for TAPSE (1.45, p=0.071 and 1.00, p=0.82, respectively). Conclusion RV strain performed using 2-dimensional STE provides important prognostic value within a large and mixed population of PH patients.